Taxol® (paclitaxel) has been shown to have excellent antitumor activity in vivo. Taxol® has been employed in the treatment of a variety of cancers, including breast, ovarian and lung cancer.
The clinical use of doxorubicin (DOX), an anthracycline, in cancer therapy is limited by the possible development of chronic cardiomyopathy and congestive heart failure, especially when the cumulative dose exceeds about 500 mg/m2. Combining DOX with paclitaxel (PTX) has been shown to cause an unacceptable incidence of cardiac events at cumulative doses of the anthracycline below about 500 mg/m2. Because of such enhancement in cardiotoxicity, the cumulative dose of DOX must be reduced to about 360 mg/m2 when the anthracycline is given in combination with PTX. There are reports indicating that combination therapy with docetaxel (DCT) would not increase the cardiotoxicity of DOX. It is noteworthy, however, that very few patients in these studies were exposed to cumulative doses of DOX higher than about 360-400 mg/m2.
Two-electron reduction of the carbonyl group in the side chain of DOX converts the anthracycline to a dihydroxy (secondary alcohol) metabolite called doxorubicinol (DOXol). This reaction is catalyzed by NADPH oxidoreductases located in the cytosol. There is growing evidence that DOXol may be an important mediator of cardiotoxicity. One-electron reduction of the quinone moiety in the tetracyclic ring of DOX generates a semiquinone that oxidizes to regenerate the parent anthracycline by reducing oxygen to free radicals. This reaction is catalyzed by several reductases, including the microsomal NADPH cytochrome P-450 reductase and the mitochondrial NADH dehydrogenase. The role of free radicals in anthracycline-induced cardiotoxicity is controversial, but these species may play a more definite role when synergized by the concomitant formation of DOXol.
As those experienced in the field of oncology appreciate, a need exists for combination chemotherapy regimens having improved efficacy and safety.